Medulloblastoma (MB) is a neuroepithelial tumor of the cerebellum and is the most common central nervous system (CNS) malignancy in children. While survival improved dramatically over the past two decades, approximately one-third remain refractory to treatment and current regimens result in long-term devastating sequelae. MBs, like several other tumors, are thought to be derived from a cell with stem-like features, so-called cancer stem cells (CSCs). Stem-like cancer cells have been demonstrated within several tumors of the CNS. However, it is unclear whether the tumors are derived from these cells, are simply recruited to the site by chemotactic factors released by the tumor stroma or whether cells within the tumor mass de-differentiate into these stem-like cells. The possibility that tumors are derived from stem-like populations has major implications for therapy since most anti- tumor regimens are geared towards elimination of cells with high proliferative index, which is not a feature of some particular classes of precursor cells such as the type B nestin+ precursor cells. In this study the cellular origins of MB will be evaluated through conditional ablation of nestin+ precursor cells in a mouse model of the disease. We will also evaluate the role of Ccrk in mouse neural development and the roles of BROMI and CCRK in the proliferation and tumorigenic potential of human desmoplastic MB cells. Our group recently showed that Bromi affects cilia morphology and Shh signaling and that it associates with and stabilizes Ccrk. This work will advance our understanding of the pathogenic mechanism of an important CNS tumor and may ultimately facilitate development of novel diagnostic, prognostic and therapeutic tools as well as enable deeper insight into the mechanistic details of the ubiquitous Shh signaling pathway. Moreover, since Shh misregulation occurs in a quarter of all human tumors and some aspects of MB pathogenesis may be generalizable to other CNS neoplasms, the results from this study may have far-reaching implications. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common pediatric brain malignancy with dismal long-term survival and devastating sequelae in survivors. This project will address both cellular origins and molecular requirements for the development and maintenance of the disease. Results garnered from this work will deepen our understanding of medulloblastoma, potentially other CNS tumors and may reveal novel diagnostic, prognostic and therapeutic tools.